CONTENTS
- Rapid reference 🚀
- Definition & classification
- Diagnosis
- Causes of acute liver failure
- Laboratory & imaging evaluation
- Treatment
- Podcast
- Questions & discussion
- Pitfalls
diagnostics
- Order initial test panels as listed below. 📖
- Serial labs (including: ammonia levels, INR, fibrinogen, glucose, and lactate).
basic supportive measures
- Medication review:
- Dose adjust hepatically cleared medications.
- D/C any acetaminophen orders.
- D/C nephrotoxins.
- Consider discontinuing antihypertensives & diuretics (or dose reduction).
- Avoid sedating medications.
- N-acetylcysteine infusion. 📖
- Hemodynamic support: vasodilatory shock may occur, which should be aggressively treated (e.g., early vasopressor for target MAP>75 mm). 📖
- Low threshold for lactulose to treat any constipation. 📖
- Follow fingerstick glucose and avoid hypoglycemia. 📖
- Stress ulcer prophylaxis: low threshold for patients with coagulopathy.
definition of acute liver failure requires:
- (1) Synthetic liver failure (INR > 1.5) with hepatic encephalopathy.
- Coagulopathy alone (without encephalopathy) is termed acute liver injury.(33664980)
- (2) No underlying cirrhosis.
- (3) Hepatic encephalopathy beginning within roughly <12weeks.
subclassification of acute liver failure based on speed of disease progression
- Hyperacute liver failure (HALF): <1 week from jaundice to encephalopathy.
- Common causes include acetaminophen or viral hepatitis.
- Carries a higher risk of cerebral edema and multiorgan dysfunction.
- If patients can survive the immediate illness, they may have a greater likelihood of experiencing hepatic recovery and thus avoiding transplantation.
- Acute liver failure: 1-4 weeks from jaundice to encephalopathy.
- Subacute liver failure (SALF): 4-12 weeks from jaundice to encephalopathy.
- Indicates a smouldering disease process.
- This is less likely to cause cerebral edema or cause immediate death. Clinically this disease process may mimic cirrhosis (e.g., a gradual process with ascites and splenomegaly).
- There is a much lower likelihood of hepatic recovery, so patients are more likely to ultimately require transplantation.(33664980)
signs & symptoms
- Jaundice, although this may not be prominent.
- Encephalopathy, graded as follows:
- Grade I: Patient shows altered behavior with normal level of consciousness, reduced attention span.
- Grade II: Patient displays altered behavior with disorientation, drowsiness.
- Grade III: Patient is confused, incoherent, mostly sleeping but arousable to painful stimuli.
- Grade IV: Patient is comatose and unresponsive to pain.
- Other findings may include:
- Nausea/vomiting, anorexia.
- Right upper quadrant pain.
- Pruritus.
- Distension due to ascites.
laboratory indications of hepatic failure
- Labs suggesting active or impending hepatic failure may include:
- INR >1.5
- Marked hyperbilirubinemia.
- Severe elevation of transaminases.
- Frank metabolic failure of the liver may eventually cause:
- Lactic acidosis (although there are many potential causes of lactic acidosis, discussed here).
- Hypoglycemia.
- Hyperammonemia.
neuroimaging findings in acute hyperammonemic encephalopathy
- (1) The classic finding is T2/FLAIR hyperintensity with diffusion restriction involving the insular gyri and cingulate gyri (with relative sparing of the occipital lobes and perirolandic region; figure below). Basal ganglia and thalami may also be involved.(31589567)
- (2) Less severe cases may spare the cortex. These may only involve the thalami, posterior limb of the internal capsule, dorsal brainstem, and sometimes periventricular white matter.(31589567)
- (3) Acute toxic leukoencephalopathy may occur as the sole imaging finding.(31589567)
most common causes
- Acetaminophen.
- Other drugs & toxins:
- Numerous drugs are implicated. Occasional clues to idiosyncratic drug-induced hepatitis may include rash, fever, and/or eosinophilia. Some commonly implicated medications are listed below, but for a more complete reference see livertox.nih.gov.(33664980) Non-acetaminophen drug-induced liver injury often doesn't resolve, so transplantation may be an earlier consideration.(31885843)
- Antimicrobials account for ~50% (e.g., isoniazid, beta-lactams).(35574981)
- Chemotherapy.
- NSAIDs.
- Statins.
- Carbamazepine.
- Phenytoin.
- Substance use, including cocaine and MDMA (“ecstasy”).
- Amanita phalloides mushroom poisoning.
- Always ask patients about over the counter medications and herbals/supplements.
- (Note: Alcohol does not cause acute liver failure; rather, this is classified as acute-on-chronic liver failure).
- Numerous drugs are implicated. Occasional clues to idiosyncratic drug-induced hepatitis may include rash, fever, and/or eosinophilia. Some commonly implicated medications are listed below, but for a more complete reference see livertox.nih.gov.(33664980) Non-acetaminophen drug-induced liver injury often doesn't resolve, so transplantation may be an earlier consideration.(31885843)
- Viral hepatitis (mostly HAV and HBV):
- HAV is usually self-limited, but an cause ALF.
- HBV can cause ALF, especially reactivation of chronic HBV in the context of chemotherapy or immunosuppression.
- HEV is more common in some areas, especially in the context of pregnancy.
- Herpesviruses:
- HSV can occur in immunocompetent patients
- CMV, EBV, or VZV in immunosuppression.
- Autoimmune hepatitis.
less common causes
- Wilson's disease.
- Budd-Chiari syndrome (hepatic vein thrombosis).
- Pregnancy-associated:
- Acute fatty liver of pregnancy.
- Preeclampsia/HELLP syndrome.
- Ischemic hepatitis:
- May especially occur in presence of biventricular dysfunction, causing congestion and poor perfusion; frank hypotension isn't always noted.
- Most patients improve with supportive management. Liver transplant is rarely, if ever, indicated.(35574981)
- Hyperthermia (including heat stroke).
- Malignant infiltration of the liver (e.g., lymphoma or metastatic adenocarcinoma).
- Veno-occlusive disease following bone marrow transplantation.
- Hemophagocytic lymphohistiocytosis (HLH).
- Reye's Syndrome.
labs to guide management
- Complete blood count.
- Chemistries, including magnesium and phosphate.
- Liver function tests (including alkaline phosphatase).
- Coags (including INR, PTT, fibrinogen, thromboelastography).
- Lactate.
- Ammonia (>150 uM correlates with increased risk of herniation).(17685471)
- Beta-HCG if potentially pregnant.
basic investigation package to evaluate the etiology of ALF
- 📦 Acetaminophen level.
- 📦 HIV.
- 📦 HAV IgM.
- 📦 HBV panel (surface antigen, surface antibody, IgM anti-core antibody, HBV PCR).
- 📦 HCV antibody.
- 📦 HSV panel (HSV IgM, HSV-1 and HSV-2 PCR).
- 📦 Autoimmune panel (ANA, anti-smooth muscle antibody, immunoglobulin levels).
- 📦 Right upper-quadrant ultrasound (including Doppler to exclude Budd-Chiari).
additional labs to consider for evaluation of etiology
- If concerned for acute HCV: HCV RNA.
- In immunocompromised: CMV IgM and PCR; EBV IgM and PCR; VZV.
- If recent travel to endemic area or pregnancy: HEV IgM antibody.
- Wilson's disease:
- Suggested if:(35574981)
- Alkaline phosphatase (in IU/L) is less than four times the bilirubin (in mg/dL)
- Coombs negative hemolytic anemia.
- If suspected, check serum copper level.
- Suggested if:(35574981)
consider transfer to a liver transplant center
- Patients with acute hepatic failure can deteriorate rapidly. Especially if the patient is a potential transplant candidate, it is often safest to pursue early transfer to a liver transplant center.
- Criteria for transfer vary widely. The most important aspect is early and clear communication between centers regarding eligibility and timing of transfer.
treatment of any identifiable cause of hepatic failure
- Medication/toxin exposures may require specific therapy:
- Review all medications regarding potential hepatotoxicity (compare to livertox.nih.gov).
- Discontinue any potentially hepatotoxic medications.
- ⚠️ Make sure to discontinue PRN acetaminophen orders (which are often part of prefabricated order sets).
- Steroid therapy is occasionally indicated:
- Antiviral therapy for acute HBV, HSV, VZV, or CMV.
N-acetylcysteine
- N-acetylcysteine should be given for both acetaminophen and non-acetaminophen liver failure.(32068578)
- Acetaminophen toxicity is the #1 cause of liver failure in many developed nations. This may result from suicide attempts or medication errors (e.g., simultaneous use of several acetaminophen-containing cold medications).
- N-acetylcysteine improves transplant-free survival even in hepatic failure not due to acetaminophen toxicity.(19524577, 23325162)
- Generally, the regimen is the same as for acetaminophen intoxication:
- N-acetylcysteine is easiest to administer intravenously. MDCalc has a calculator for the dose.
- Repeat the third dose (as a continuous infusion) until the patient is improving (and, if the patient did take acetaminophen, until the acetaminophen level is negative). If improvement doesn't occur, the infusions shouldn't be continued longer than five days.(32068578)
- Acute hepatic failure tends to cause a vasodilatory shock state. Clinically this may be nearly indistinguishable from septic shock (if doubt exists regarding the possibility of septic shock, cultures should be obtained and empiric broad-spectrum antibiotics initiated).
- Norepinephrine is often a front-line pressor.
- Targeting a high Bp (e.g., MAP>75 mm) may be beneficial. This may promote cerebral perfusion in the face of elevated intracranial pressure, and may also be beneficial to renal perfusion in patients with hepatorenal physiology.(31915608, 30694840)
- Acute hepatic failure may cause relative adrenal insufficiency, so stress-dose steroids should be an early consideration.(28131021)
- If hypovolemic, 5% albumin might be a preferred fluid.(31394283, 33205036)
- There should be a low threshold to discontinue antihypertensives & diuretics.
- Intubation may be required in patients with worsening hepatic encephalopathy, to achieve several purposes:
- Airway protection from aspiration.
- Avoid hypercapnia (which could worsen ICP elevation); for intubated patients, target a low-normal PaCO2.(28417882)
- Propofol sedation may reduce intracranial pressure.
- For patients with deteriorating encephalopathy and worsening hepatic function, there is little role for BiPAP (given high risks of deterioration and aspiration).
- Stress ulcer prophylaxis should be considered, even in nonintubated patients.
- Avoid constipation, with a low threshold to initiate lactulose as the cathartic agent of choice.
nutritional support
- Standard protein targets can generally be utilized (1.2 grams/kg IBW/day). 📖(32058375)
- Monitoring ammonia may be useful to avoid exacerbation of hyperammonemia.(28417882) For marked hyperammonemia (e.g., >150 uM/L) and high-grade encephalopathy, temporarily suspend feeding, until ammonia levels are controlled.(32068578)
basic supportive care
- Avoid nephrotoxins.
- Treat electrolyte abnormalities (especially hypokalemia or sodium abnormalities, if they seem to be contributing to encephalopathy).
- Hypokalemia may increase renal ammoniagenesis, so it should be treated promptly.
treat acute kidney injury early (defined by Cr rise >0.3 mg/dL or 1.5-times baseline)
- Consider empiric therapy for hepatorenal syndrome, including albumin and vasopressors (more on this here).
- Early initiation of dialysis may assist in ammonia clearance, so this is recommended by the SCCM guidelines and European guidelines.(28417882, 32058375) Early renal replacement therapy may be used to target an ammonia level <100 uM/L.(32068578) Continuous renal replacement is preferred over intermittent dialysis, to avoid rapid electrolyte shifts which may cause fluctuations in intracranial pressure. Patients are often hyperosmolar due to the accumulation of solutes (e.g., urea), so osmotherapy with hypertonic saline may be considered to mitigate drops in tonicity that occur when initiating dialysis.(32487902)
- Citrate is usually avoided, since it may accumulate in the context of hepatic failure. If anticoagulation is needed, heparin is generally preferred.
- Bacterial superinfection is a substantial problem. However, these typically occur later on during the ICU course (e.g., after >1 week).
- There should be a low threshold for obtaining cultures and initiating empiric antibiotics (especially if septic shock is suspected).
DVT prophylaxis is generally indicated
- Despite the elevated INR, patients in acute liver failure have a tendency towards coagulation (more-so than patients with chronic liver disease).(32334790)
- When doubt exists (e.g., in patients with profoundly elevated INR), thromboelastography may be helpful to understand the patient's coagulation balance. If the R-time is normal or low, then DVT prophylaxis should be administered.
management of coagulopathy
- (1) Usually avoid giving fresh frozen plasma (FFP), for the following reasons:
- Giving plasma makes it impossible to use the INR as a measurement of hepatic synthetic function.
- Most patients with elevated INR aren't truly coagulopathic.
- Fresh frozen plasma may be indicated for patients with clinical bleeding and enzymatic coagulopathy on thromboelastography (i.e., prolonged R-time). 📖
- (2) Consider repletion of very low fibrinogen levels:
- If the fibrinogen level decreases substantially (e.g., <100 mg/dL), repletion with cryoprecipitate or fibrinogen concentrate may be reasonable (especially if there is concomitant thrombocytopenia). Substantial hypofibrinogenemia may cause a risk of intracranial hemorrhage.
empiric vitamin K
- Consider 10 mg vitamin K intravenously (to exclude vitamin K deficiency and thereby promote accurate prognostication based on INR values).
- Realistically, vitamin K usually has minimal effect among patients with acute liver failure (who rarely will be vitamin K deficient).
avoid hypoglycemia
- Hypoglycemia can result from the liver's inability to synthesize glucose.
- Follow glucose levels regularly, especially if patients are NPO.
- Don't aggressively control hyperglycemia.
- Intubated patients should ideally receive nutrition, if possible (see above).
- There should be a low threshold to initiate a dextrose infusion to prevent hypoglycemia (e.g., D10W via peripheral line, or higher concentrations via central line).
The greatest life threat is often acute hepatic encephalopathy, which is frequently associated with increased intracranial pressure and herniation. This is far more dangerous than hepatic encephalopathy seen in chronic cirrhosis (which isn't associated with cerebral edema or herniation).
basic measures
- Avoid sedating medications (that may cloud the picture or exacerbate encephalopathy).
- Lactulose has not been proven to reduce mortality, but it may decrease ammonia levels and remains a rational therapy (if it can be safely tolerated).
diagnosis of ICP elevation
risk factors for ICP elevation
- Ammonia levels may be the strongest risk factor, as this seems to be a primary driver of cerebral edema:
- >100 uM/L predicts the onset of severe hepatic encephalopathy.
- >150-200 uM/L correlates with risk of herniation.(30694840)
- Renal failure.
- Renal replacement therapy (more severe renal injury results in greater ammonia retention).
- Hypotension requiring vasopressor support.
- Younger age.
- Hyperacute presentation (shorter duration from jaundice to encephalopathy).
clinical findings that may be seen
- The main sign of ICP elevation is severe encephalopathy.
- Hypertension, bradycardia, and abnormal respiratory patterns (Cushing's Triad).
- Mydriasis.(28417882)
- Decerebrate posturing.
imaging studies
- CT is insensitive. Eventually, diffuse narrowing of sulci and compression and effacement of ventricles and cisterns becomes apparent.(Shutter 2019)
- Optic nerve ultrasonography may be useful. 🌊
- Transcranial Doppler is another option, if serial high-quality doppler studies are available .
invasive ICP monitoring
- This is controversial. It may be considered in highly selected patients who are at the greatest risk for elevated intracranial pressure.
- Perhaps the most useful role might be as a prognostic tool while awaiting transplantation (cerebral perfusion pressure <40 mm for >4 hours predicts irreversible brain injury).
management of ICP elevation
basic interventions
- Target low-normal pCO2.(28417882)
- Target a high-normal sodium level (140-145 mM).
- Avoid fever: Low threshold to institute definitive temperature control using an external adaptive cooling system (e.g., Arctic Sun system targeted to 36C).
- Avoid hypoglycemia (may be especially dangerous in the context of brain injury). 📖
- Sedation with propofol (may improve ICP and also prevent seizures).
- Avoid hypotension (as this may cause a profound drop in the cerebral perfusion pressure). It might be reasonable to target a somewhat higher MAP than usual to maintain an adequate cerebral perfusion pressure (e.g., >75-80 mm). If the ICP is known, the cerebral perfusion pressure (CPP) may be maintained at >60 mm.📖
management of hyperammonemia
- Hyperammonemia seems to be the primary driver of elevated intracranial pressure in acute liver failure.
- Renal replacement therapy may be useful to clear ammonia.(32334790, 30694840)
- Continuous renal replacement therapy initiation when ammonia levels are >150 uM/L may be associated with improved survival.(32068578)
- Continuous renal replacement is preferred over intermittent hemodialysis, to prevent rapid electrolyte shifts.
- Rifaximin combined with either lactulose or polyethylene glycol may help reduce ammonia absorption from the bowel (discussed further in the chapter on hepatic encephalopathy 📖).
seizure management
- Subclinical seizure is often present in grade III-IV encephalopathy, so there should be a low threshold for obtaining video EEG.
- Prophylactic antiepileptic agents are generally not recommended. However, one trial did find that prophylactic phenytoin reduced seizures and cerebral edema among patients with grade III-IV encephalopathy. Thus, seizure prophylaxis could be reasonable among patients with advanced encephalopathy, if video EEG is unavailable.(10960446)
- Propofol is a preferred sedative among intubated patients, with the advantage of providing antiepileptic activity.
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- Any patient with acute hepatic failure should receive a consultation with transplant hepatology and/or discussion with a regional liver transplant center.
- Give N-acetylcysteine to all hepatic failure patients. Don't allow the infusion to stop until the patient has recovered.
- Do not fail to aggressively diagnose and treat hepatorenal syndrome. Supporting the kidney function may promote ammonia clearance and thereby prevent other organ failures (e.g., hepatic encephalopathy).
- Beware of acute hepatic encephalopathy and consider initiation of treatment early.
- Consider video EEG for intubated patient with hepatic encephalopathy. Seizure is a common event in this context, which may exacerbate ICP elevation and promote herniation.
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References
- 17685471 Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology. 2007 Dec;46(6):1844-52. doi: 10.1002/hep.21838. [PubMed]
- 19524577 Lee WM, Hynan LS, Rossaro L, et al; Acute Liver Failure Study Group. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009 Sep;137(3):856-64, 864.e1. doi: 10.1053/j.gastro.2009.06.006 [PubMed]
- 23325162 Singh S, Hynan LS, Lee WM; Acute Liver Failure Study Group. Improvements in hepatic serological biomarkers are associated with clinical benefit of intravenous N-acetylcysteine in early stage non-acetaminophen acute liver failure. Dig Dis Sci. 2013 May;58(5):1397-402. doi: 10.1007/s10620-012-2512-x [PubMed]
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- Shutter, L. A., Molyneaux, B. J. (2019). Neurocritical care. Oxford University press.
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